1. Field of the Invention
The present invention relates to the topical ophthalmic use of sulfur-containing steroids in the treatment of ophthalmic inflammatory disorders. More particularly, this invention relates to the treatment of ophthalmic inflammatory disorders with C-21 thioether anti-inflammatory steroids which do not cause any significant increase in intraocular pressure as a side effect.
2. Discussion of Related Art
Anti-inflammatory steroids, such as hydrocortisone, prednisolone, dexamethasone, and fluorometholone, are very useful in controlling a wide range of ophthalmic inflammatory conditions. One of the troubling aspects of steroid anti-inflammatory drugs for topical ophthalmic use, however, is the elevation of intraocular pressure (IOP). This side effect precludes the use of these drugs in steroid responders and/or glaucomatous individuals. In either case patients with acute or chronic inflammatory diseases may not be aware of their condition, only to discover it following initiation of treatment. In the first case steroid responders will increase the IOP to dangerous levels or precipitate asteroid glaucoma, both of which will go undetected unless the ophthalmologist examines eye pressure during the treatment course. In the second case and if a chronic inflammatory condition exists, severe damage to the optic nerve can occur leading to blindness. Further discussion of this side effect is presented in an article by Phillips, et al., The Lancet, 767-768 (Apr. 7, 1984).
The exact nature and sequence of events leading to IOP elevation by steroids during treatment of acute or chronic inflammatory episodes is unknown. It is established, however, that topical ophthalmic application of glucocorticoid steroids in which the C-21 methylene hydroxy group remains intact and unprotected, such as dexamethasone, will elevate IOP. It is also established that treatment of inflammatory eye disorders with short chain esters (1-5 carbon atoms) at this location do not protect against the IOP side effect due to hydrolysis of the ester back to the primary alcohol (Boltralik, Invest. Ophthalmol. 13: (Supplement): 78 1974). Esterification at C-21 merely increases the partition coefficient of the drug which enhances the amount of drug absorbed/unit dose.
Among other known derivatives of glucocorticoid steroids are C-21 thioesters. British Patent No. 1,475,795, and U.S. Pat. Nos. 3,687,942, 4,427,671, and 5,021,408 teach C-21 thioesters as anti-inflammatory drugs, some of which avoid systemic side effects typically caused by glucocorticoid steroids. British Patent No. 1,475,795 discloses the local treatment of ophthalmological illnesses of an inflammatory and/or allergic nature.
Also among known derivatives of glucocorticoid steroids are C-21 thioethers which are useful as intermediates in making other compounds. U.S. Pat. No. 3,959,260 teaches their use as intermediates in making anaesthetic steroids. U.S. Pat. No. 3,803,133 teaches the use of C-21 thioethers as intermediates in making anti-inflammatory sulfinyl steroids.
Milioni et al., Arzneim-Forsch/Drug Res. 41:741-743 (1991), teach a C-21 thioether derivative, namely 21-thiol-9.alpha.-fluoro-11.beta.,17.alpha.-dihydroxy-16.alpha.-methyl-3,2 0-dione-21-acetylamino cysteine, as a topical dermatological anti-inflammatory agent lacking systemic side-effects. Mitsukuchi et al., Chem. Pharm. Bull., 37:3286-3293 (1989), teach certain C-21 thio derivatives as topical dermatological anti-inflammatory agents. Neither Milioni et al. nor Mitsukuchi et al. teach ophthalmic use of their respective C-21 derivatives.
The topical dermatological use of C-21 thioethers as anti-inflammatory steroids is also taught in European Patent Application No. 208,202 and U.S. Pat. No. 4,861,765. These references teach C-21 thioethers having reduced systemic side-effects after absorption through the skin.
U.S. Pat. No. 4,913,852 teaches compounds obtained from the associative synthesis of sulfur-containing or sulfur-free amino acids with steroidal derivatives, having glucocorticoid and anti-inflammatory properties. These compounds are taught for various applications, "particularly in the cutaneous and ophthalmic fields." One of the classes of compounds taught by the '852 patent is amino acid-terminated C-21 thioethers. No mention is made of any C-21 thioether not having a terminal amino acid group, nor of any IOP side-effect reduction.
Recent efforts to develop improved steroidal anti-inflammatory drugs for topical ophthalmic use have focused on eliminating the IOP side-effect mentioned above while maintaining anti-inflammatory activity. U.S. Pat. No. 5,223,493 teaches one solution, namely the use of C-21 ether derivatives of dexamethasone. These C-21 ether derivatives retain anti-inflammatory activity and successfully suppress the IOP elevation side effect common to most anti-inflammatory glucocorticoids such as dexamethasone, prednisolone, fluocinolone, etc.
What is needed are additional topically administrable, anti-inflammatory corticosteroids which are useful in treating ophthalmic inflammatory disorders and which do not cause a significant IOP increase as a side-effect.